A B cell intrinsic defect initiates autoimmunity in New Zealand Black chromosome 13 congenic mice (49.21)

Abstract

Abstract Introgression of a New Zealand Black (NZB) chromosome 13 (c13) interval onto a lupus-resistant C57BL/6 (B6) background (denoted, B6.NZBc13) is sufficient to produce many of the hallmarks of lupus. To characterize the immune defects leading to these abnormalities observed in B6.NZBc13 mice, bone marrow (BM) chimeras and BCR transgenic mice were produced. In BM chimeras, transfer of B6.NZBc13 BM cells was sufficient to transfer autoimmunity. Interestingly, in mixed BM chimeras the abnormal T and B cell activation as well as DC expansion was observed in both B6 and B6.NZBc13 derived cells; but with greater B cell activation in B6.NZBc13 derived cells. When an anti-HEL Ig transgene was crossed onto the congenic background disease was abrogated and the abnormal cellular phenotypes normalized. Although tolerance was retained in anti-HEL Ig/soluble HEL double transgenic mice, increased numbers of 'edited' cells were seen in the periphery. B cell function studies revealed altered phosphorylation of signaling molecules downstream of the BCR. These findings indicate the presence of a BM-cell intrinsic defect on NZB c13 that can be localized to a B cell defect, which is necessary to initiate the autoimmune phenotype in B6.NZBc13 mice.